Threshold effects in gene regulation: when some is not enough.

Understanding a complex system requires more than assembling a parts list and wiring the parts together. We also need to understand the functional consequences of the connections, the biochemical properties of the parts and their interactions, the timing of events in a dynamic circuit, and the response of the system to stimuli if we hope to predict systems behavior and the consequences of changes in the system. In a recent issue of PNAS, Kobiler et al. (1) took an important step in this direction for one of the best-understood model gene regulatory circuits, that of bacteriophage λ. For decades, studies on λ have pioneered this progression toward a systems-level description of a complex regulatory circuit (2, 3). At the same time, since the early days of λ biology, outsiders have been bewildered by the tendency of λ workers to use an apparently endless stream of mutations and multiple-mutant combinations to prove their points. Kobiler et al. (1) offer a relatively mild dose of this treatment, but an introduction to the λ life cycle, the players, and their interactions is helpful. An Escherichia coli cell infected with λ can follow either of two alternative pathways (Fig. 1 A ). The choice between these is termed the lysis–lysogeny decision (4, 5). In the lytic pathway (blue in Fig. 1 A ), the cell executes a pattern of viral gene expression (Fig. 1 B ), replicates the viral DNA, makes ≈100 new virions, and finally lyses. In the lysogenic pathway (green in Fig. 1 A ), by contrast, the viral genome sets up housekeeping in the host; the lytic genes are repressed by CI repressor, and the viral DNA is physically integrated into the host genome. Once established, the lysogenic state is extremely stable; CI can repress the lytic genes indefinitely. However, this state can switch to …